Edaravone

Edaravone
Clinical data
Trade names	Radicava, others
Other names	MCI-186
AHFS/Drugs.com	Monograph
MedlinePlus	a617027
License data	US DailyMed: Edaravone;
Pregnancy; category	AU: B3; ;
Routes of; administration	Intravenous, by mouth
ATC code	N07XX14 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; US: ℞-only; In general: ℞ (Prescription only);
Identifiers
	IUPAC name 5-methyl-2-phenyl-4H-pyrazol-3-one;
CAS Number	89-25-8 ;
PubChem CID	4021;
DrugBank	DB12243 ;
ChemSpider	3881 ;
UNII	S798V6YJRP;
KEGG	D01552 ;
ChEBI	CHEBI:31530 ;
ChEMBL	ChEMBL290916 ;
PDB ligand	W1P (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID9021130 ;
ECHA InfoCard	100.001.719
Chemical and physical data
Formula	C10H10N2O
Molar mass	174.203 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C1N(/N=C(\C1)C)c2ccccc2;
	InChI InChI=1S/C10H10N2O/c1-8-7-10(13)12(11-8)9-5-3-2-4-6-9/h2-6H,7H2,1H3 ; Key:QELUYTUMUWHWMC-UHFFFAOYSA-N ;
	(verify)

Edaravone, sold under the brand name Radicava among others, is a medication used to treat stroke and amyotrophic lateral sclerosis (ALS).^[4]^[5] It is given by intravenous infusion^[4] and by mouth.^[4]^[6]

The mechanism by which edaravone might be effective is unknown.^[4] The medication is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS and in stroke victims.^[7]

The most common side effects include bruising (contusions), problems walking (gait disturbances), and headaches.^[6]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[8]

Medical uses

Edaravone is used to help people recover from stroke in Japan,^[9] and is used to treat ALS in the US and Japan.^[4]^[7]

Adverse effects

The label carries a warning about the potential for hypersensitivity reactions to edaravone, and adverse effects include bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.^[4]

The following adverse effects in at least 2% more people given the medication than were given placebo: bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.^[4]

There is no data on whether it is safe for pregnant women to take, and it is unknown if edaravone is secreted in breast milk.^[4]

Pharmacology

The mechanism by which edaravone might be effective is unknown.^[4] The medication is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process of neurodegeneration.^[7]

The half-life of edaravone is 4.5 to 6 hours and the half-lives of its metabolites are 2 to 3 hours. It is metabolized to a sulfate conjugate and a glucuronide conjugate, neither of which are active. It is primarily excreted in urine as the glucuronide conjugate form.^[4]

History

Researchers first developed the free radical scavenger edaravone in late 1980s as a treatment for stroke. The approach, introduced by Koji Abe, now at Okayama University Hospital in Japan, aimed to prevent the swelling of the brain which may occur after a stroke.^[10]

It has been marketed in Japan by Mitsubishi Pharma for stroke since 2001 and is now generic.^[9]^[11]

Mitsubishi Tanabe started a phase III clinical trial in ALS in 2011, in Japan, and by June 2015, it had been approved for that use in Japan. The company had received Orphan Drug Designation for edaravone from the FDA and EU by 2016.^[12]

It was approved for ALS in the US in 2017, based on a small randomized controlled clinical trial with people who had early-stage ALS in Japan, who were administered the medication for 6 months; it had failed two earlier trials in people with all stages of ALS.^[4]^[7]

In May 2017, I.V. edaravone was approved by the FDA to treat people with amyotrophic lateral sclerosis (ALS) in the United States.^[13] The FDA approval was conditioned on Mitsubishi Tanabe completing several additional studies to clarify the risks of cancer and liver disease, among other effects of the medication.^[14]^[15]

A formulation of edaravone by mouth, which is a mixture of edaravone and SBE-HP-βCD,^[16] has been under development by Ferrer (called FAB122) and licensed by Treeway (called TW001) for ALS. As of 2015, they successfully completed a Phase I trial and received orphan status in the US and in the European Union.^[17] Ferrer reported on 10 January 2024 that the Phase III ADORE clinical trial (EudraCT 2020-003376-40 / NCT05178810) of FAB122/TW001 in ALS did not meet the primary or key secondary study endpoints.^[18]

A different oral formulation of edaravone from Mitsubishi Tanabe Pharma America (MT1186 or MT-1186) was approved for medical use in the United States in May 2022.^[4]^[6]^[19] The effectiveness of oral edaravone is based on a study that showed comparable levels of oral edaravone in the bloodstream to the levels from the IV formulation of edaravone.^[6] The efficacy of edaravone for the treatment of ALS was previously demonstrated in a six-month clinical trial that served as the basis for approval in 2017.^[6] In that trial, 137 participants were randomized to receive edaravone or placebo. At week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving placebo.^[6] An analysis of real-world data of 194 patients from 12 ALS clinics of the intravenous formulation, failed to reproduce the effect.^[20] A global Ph3b study with the oral formulation was halted in 2023.^[21]

Society and culture

Economics

The price for the medication when it launched in Japan for stroke in 2001, was set by the Japanese government at 9,931 yen/ampule.^[22]

When the medication launched in Japan for ALS in 2001, the price was $35,000; the price in Japan in 2017 was $5,000, the US price at launch was around $145,000.^[11] In the US the medication was approved for all people with ALS but it was unclear at approval whether insurers would agree to pay for the medication for all people with ALS, or only people in the early stages of the disease.^[11]^[23]

Brand names

Brand names include Radicut, Radicava, Xavron.^[24]

References

^ ^a ^b "Radicava". Therapeutic Goods Administration (TGA). 24 February 2023. Archived from the original on 24 February 2023. Retrieved 7 April 2023.
^ "Radicava edaravone 30 mg/20 mL concentrated injection ampoule (375455)". Therapeutic Goods Administration (TGA). 16 February 2023. Archived from the original on 8 April 2023. Retrieved 7 April 2023.
^ "Regulatory Decision Summary for Radicava". 23 October 2014. Archived from the original on 7 June 2022. Retrieved 7 June 2022.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m "Radicava- edaravone injection Radicava ORS- edaravone kit". DailyMed. 12 May 2022. Archived from the original on 27 January 2022. Retrieved 27 May 2022.
^ Bailly C, Hecquet PE, Kouach M, Thuru X, Goossens JF (May 2020). "Chemical reactivity and uses of 1-phenyl-3-methyl-5-pyrazolone (PMP), also known as edaravone". Bioorganic & Medicinal Chemistry. 28 (10): 115463. doi:10.1016/j.bmc.2020.115463. PMID 32241621. S2CID 214766793.
^ ^a ^b ^c ^d ^e ^f "FDA Approves Oral Form of ALS Treatment". U.S. Food and Drug Administration (FDA). 12 May 2022. Archived from the original on 12 May 2022. Retrieved 12 May 2022. This article incorporates text from this source, which is in the public domain.
^ ^a ^b ^c ^d Petrov D, Mansfield C, Moussy A, Hermine O (2017). "ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?". Frontiers in Aging Neuroscience. 9: 68. doi:10.3389/fnagi.2017.00068. PMC 5360725. PMID 28382000.
^ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Archived from the original on 23 October 2020. Retrieved 16 September 2020.
^ ^a ^b Miyaji Y, Yoshimura S, Sakai N, Yamagami H, Egashira Y, Shirakawa M, et al. (2015). "Effect of edaravone on favorable outcome in patients with acute cerebral large vessel occlusion: subanalysis of RESCUE-Japan Registry". Neurologia Medico-Chirurgica. 55 (3). Tokyo: 241–247. doi:10.2176/nmc.ra.2014-0219. PMC 4533339. PMID 25739433.{{cite journal}}: CS1 maint: overridden setting (link)
^ "FDA Approves Edaravone as a Treatment for ALS". Research ALS. Archived from the original on 12 February 2019. Retrieved 10 May 2017.
^ ^a ^b ^c Herper M. "The First ALS Drug In 22 Years Is Approved -- And It Costs 4 Times What It Does In Japan". Forbes. Archived from the original on 6 May 2017. Retrieved 10 May 2017.
^ Lane EJ (20 April 2016). "Mitsubishi Tanabe says ALS drug meets PhIII endpoint". FiercePharma. Archived from the original on 13 February 2019. Retrieved 13 May 2017.
^ "FDA approves drug to treat ALS". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 8 May 2017. Retrieved 7 May 2017.
^ "NDA 209176 Approval letter" (PDF). U.S. Food and Drug Administration (FDA). 5 May 2017. Archived (PDF) from the original on 10 May 2018. Retrieved 13 May 2017.
^ "Radicava (edaravone) Injection". U.S. Food and Drug Administration (FDA). 20 June 2017. Archived from the original on 13 May 2022. Retrieved 12 May 2022.
^ Rong WT, Lu YP, Tao Q, Guo M, Lu Y, Ren Y, et al. (February 2014). "Hydroxypropyl-sulfobutyl-β-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes". Journal of Pharmaceutical Sciences. 103 (2): 730–742. doi:10.1002/jps.23807. PMID 24311389.
^ "Edaravone oral". AdisInsight. Archived from the original on 7 July 2017. Retrieved 13 May 2017.
^ "Ferrer reports top-line results from Phase III ADORE study in ALS | Ferrer". www.ferrer.com. Archived from the original on 8 March 2024. Retrieved 8 March 2024.
^ NDA Approval fda.gov Archived 13 May 2022 at the Wayback Machine
^ Witzel S, Maier A, Steinbach R, et al. Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022;79(2):121–130. doi:10.1001/jamaneurol.2021.4893
^ Media_MTPA@mt-pharma-us.com (1 August 2023). "Press Releases". Mitsubishi Tanabe Pharma America. Archived from the original on 8 March 2024. Retrieved 8 March 2024.
^ "Launching of Radicut Injection. 30 mg" (Press release). Mitsubishi-Tokyo Pharmaceuticals via Evaluate. 23 May 2001. Archived from the original on 3 July 2022. Retrieved 9 May 2017.
^ Grady D (5 May 2017). "A Second Drug Is Approved to Treat A.L.S." The New York Times. Archived from the original on 4 April 2018. Retrieved 8 May 2017.
^ Makam AN, Suh K, Nikitin D, Carlson J, Richardson M, Mohammed R, et al. (4 August 2022). "AMX0035 and Oral Edaravone for Amyotrophic Lateral Sclerosis: Evidence Report" (PDF). Institute for Clinical and Economic Review: D6.